BACKGROUND: Treatment for patients with bilateral adrenal tumours and cortisol excess is not standardised and poses a therapeutic dilemma. Untreated cortisol excess is associated with cardiometabolic morbidity and mortality, but bilateral adrenalectomy causes adrenal insufficiency and possibly life-threatening adrenal crises. Data on cardiovascular outcomes by treatment modality are scarce. In this study we aimed to evaluate mid-term and long-term clinical and biochemical outcomes in patients with bilateral adrenal tumours and cortisol excess by treatment strategy and diagnosis. 

METHODS: This retrospective, international cohort study (in 30 centres across 10 countries in Europe plus Singapore and the USA) included patients with bilateral adrenal tumours of 10 mm or larger, post-dexamethasone serum cortisol concentration of 50 nmol/L or higher, and at least 36 months of follow-up, with data collection beween Feb 2, 2024, and Jan 31, 2025. Patients were excluded if they had adrenocorticotropin hormone (ACTH)-dependent cortisol excess, ACTH-dependent nodular adrenal hyperplasia, partial glucocorticoid resistance syndrome, a diagnosis inconsistent with benign adrenocortical lesions, or received systemic oral or intravenous glucocorticoids other than replacement therapy following adrenalectomy. Primary endpoints were all-cause mortality and clinical and biochemical remission rates. Secondary endpoints were the incidence of cardiovascular events, prevalence of vascular and metabolic comorbidities, and incidence of adrenal crises. 

FINDINGS: Of 629 patients who were diagnosed between Jan 1, 2000, and Jan 31, 2022, 105 (17%) had Cushing's syndrome and 524 (83%) had mild autonomous cortisol secretion (MACS), median age was 62 years (IQR 54·0-68·0), and 426 (68%) were female. 85 (81%) of 105 patients with Cushing's syndrome underwent surgery, and 384 (73%) of 524 patients with MACS received non-specific symptomatic treatment (ie, never underwent adrenalectomy or received steroidogenesis inhibitors). Over a median follow-up of 6·8 years, biochemical remission was achieved in 46 (45%) of 102 patients with Cushing's syndrome and in 67 (13%) of 517 patients with MACS. In both groups, 7% of patients died (Cushing's syndrome: seven of 105; MACS: 38 of 524) and 12% (13 of 105) of patients with Cushing's syndrome and 16% (82 of 524) of those with MACS had at least one cardiovascular event, without substantial differences across treatments. Smoking emerged as key modifiable mortality and cardiovascular risk factor in all patients, and in patients with MACS who only received non-specific symptomatic therapy, post-dexamethasone cortisol was also associated with increased mortality. Bilateral adrenalectomy led to full biochemical remission, few non-fatal adrenal crises, and improved arterial hypertension. Unilateral adrenalectomy and steroidogenesis inhibitors yielded heterogeneous biochemical outcomes and no substantial comorbidity improvement. Non-specific symptomatic treatment in MACS was associated with worsening of all investigated comorbidities.

 INTERPRETATION: Although mortality and cardiovascular event rates were similar across treatments, surgery led to better biochemical control and more favourable comorbidity outcomes.None.